US6600039B1 - Process for the preparation of n-(1,1-dimethylethyl)-4-[[5′-ethoxy-4-cis[2-(4-morpholino)ethoxy]-2′-oxospiro[cyclohexan-1,3′[h]indol]1′(2′-h)-yl]-sulfonyl]-3-methoxybenzamide and its salts - Google Patents
Process for the preparation of n-(1,1-dimethylethyl)-4-[[5′-ethoxy-4-cis[2-(4-morpholino)ethoxy]-2′-oxospiro[cyclohexan-1,3′[h]indol]1′(2′-h)-yl]-sulfonyl]-3-methoxybenzamide and its salts Download PDFInfo
- Publication number
- US6600039B1 US6600039B1 US10/030,647 US3064702A US6600039B1 US 6600039 B1 US6600039 B1 US 6600039B1 US 3064702 A US3064702 A US 3064702A US 6600039 B1 US6600039 B1 US 6600039B1
- Authority
- US
- United States
- Prior art keywords
- ethoxy
- formula
- compound
- salts
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- BHIHMDQHEVAZIW-UHFFFAOYSA-N CC1=CC=C(S(=O)(=O)N2C(=O)C3(CCC(OCCN4CCOCC4)CC3)C3=C2C=CC(C)=C3)C(C)=C1 Chemical compound CC1=CC=C(S(=O)(=O)N2C(=O)C3(CCC(OCCN4CCOCC4)CC3)C3=C2C=CC(C)=C3)C(C)=C1 BHIHMDQHEVAZIW-UHFFFAOYSA-N 0.000 description 3
- LPGCPHGGOWAOMQ-UHFFFAOYSA-N CC1=CC=C(SCl(=O)=O)C(C)=C1 Chemical compound CC1=CC=C(SCl(=O)=O)C(C)=C1 LPGCPHGGOWAOMQ-UHFFFAOYSA-N 0.000 description 3
- TVJOPMCVNDVONZ-UHFFFAOYSA-N [H]N1C(=O)C2(CCC(OCCN3CCOCC3)CC2)C2=C1C=CC(C)=C2 Chemical compound [H]N1C(=O)C2(CCC(OCCN3CCOCC3)CC2)C2=C1C=CC(C)=C2 TVJOPMCVNDVONZ-UHFFFAOYSA-N 0.000 description 3
- DQLQKTRGYUHITK-UHFFFAOYSA-N CCOc(cc1C2(CC3)CCC3OCCN3CCOCC3)ccc1NC2=O Chemical compound CCOc(cc1C2(CC3)CCC3OCCN3CCOCC3)ccc1NC2=O DQLQKTRGYUHITK-UHFFFAOYSA-N 0.000 description 1
- 0 COc1c(*)ccc(*)c1 Chemical compound COc1c(*)ccc(*)c1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/96—Spiro-condensed ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
Definitions
- the subject of the present invention is a process for the preparation of N-(1,1-dimethylethyl)-4-[[5′-ethoxy-4-cis-[2-(4-morpholino)ethoxy]-2′-oxospiro[cyclohexan- 1,3′-[3H]indol]-1′(2′H)-yl]-sulfonyl]-3-methoxybenzamide (SR 121463) of formula I
- the compound of formula I is prepared by reacting the spiro/cis-4-(beta-morpholino-ethyloxy)cyclohexan-1,3′-(5′-ethoxy)-[3H]indol-2′[1′H]one of formula II
- the subject of the invention is a process for the, preparation of the compound of the formula I
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a process for the preparation of a compound of formula (I) and the salts thereof by reacting the compound of formula (II) with the compound of formula (III), which comprises carrying out the reaction in dimethyl sulfoxide, at a temperature between 10° C. and 40° C., preferably at room temperature and transforming the resulting base of formula (I), if desired, into its salt by a method known per se.
Description
The subject of the present invention is a process for the preparation of N-(1,1-dimethylethyl)-4-[[5′-ethoxy-4-cis-[2-(4-morpholino)ethoxy]-2′-oxospiro[cyclohexan- 1,3′-[3H]indol]-1′(2′H)-yl]-sulfonyl]-3-methoxybenzamide (SR 121463) of formula I 
and its salts, compounds having vasopressine V2 antagonistic effect.
According to patent application WO 9715556 the compound of formula I is prepared by reacting the spiro/cis-4-(beta-morpholino-ethyloxy)cyclohexan-1,3′-(5′-ethoxy)-[3H]indol-2′[1′H]one of formula II 
with the 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride of formula III 
using potassium-t-butylate in tetrahydrofuran.
Because of the applied solvent (tetrahydrofuran) and reaction temperature (between −60° C. and 40° C.) it is not easy to carry out the process under industrial conditions, the yield is low, the product is contaminated, its purification requires repeated crystallization.
To our surprise, we have found that by stirring in dimethyl sulfoxide at room temperature the reaction proceeds in very good yield (85-92%). The work-up procedure is simple, while in the original process the product is obtained by extraction, in the present process the base precipitates on diluting the reaction mixture with water, and it can be filtered off. The purity of the resulting base is 93-96% and the salt formed from it is appropriately pure.
In accordance with the above, the subject of the invention is a process for the, preparation of the compound of the formula I 
and the salts thereof, by reacting the compounds of the formula II 
and III, 
which comprises carrying out the reaction in dimethyl sulfoxide at a temperature between 10° C. and 40° C., preferably at room temperature and transforming the resulting base of formula I into its salt by a method known per se.
The process according to the invention is illustrated by the following examples:
In 180 ml of dimethyl sulfoxide 26.7 g of potassium t-butylate is dissolved. After 10 minutes of stirring 74.9 g of compound II is added to the mixture, at 20-25° C., and the mixture is stirred until complete dissolution. Then rapidly, keeping the temperature below 25° C., the compound of formula III is added to the mixture. The resulting light-brown suspension is stirred at 25° C. for 1.5 hours, then it is decomposed with 700 ml of ice-water. After 1 hour of stirring, the precipitate is filtered off, suspended and washed with 2×500 ml of water, thoroughly sucked and washed with 2×100 ml of 96% ethanol. 117 g of compound of formula I is obtained, assay (by HPLC): 95.2% Yield: 90.8%.
1 mol of the base of compound I is suspended in 3-5-fold amount of ethanol and to the mixture 0.5-1 mol of acid is added. After dissolution the solution is clarified by active carbon and filtered. On cooling the salt precipitates, it is filtered off, washed with a small amount of cold ethanol and dried. Yield ranges between 87-95%. Dihydrogenphosphate monohydrate salt: mp.: 164.5° C.
| Hydrogen maleate salt | mp.: 184-185° C. | ||
| Hydrogen fumarate salt | mp.: 182-183° C. | ||
Claims (2)
1. A process for the preparation of a compound of formula I 
and the salts thereof by reacting the compound of formula II 
with the compound of formula III, 
which comprises carrying out the reaction in dimethyl sulfoxide in the presence of potassium-t-butylate, at a temperature between 10° C. and 40° C., and transforming the resulting base of formula I, if desired, into a pharmaceutically acceptable salt thereof by treatment with an acid.
2. A process according to claim 1 which comprises carrying out the reaction at room temperature.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9902376A HUP9902376A3 (en) | 1999-07-15 | 1999-07-15 | Process for producing n-(1,1-dimethyl)-4-[[s'-ethoxi-4-cis-[2-(4-morpholino)-ethoxi]-2'-oxospiro[cyclohexane-1,3'-[3h]indole]-1'(2'h)yl]-sulfonyl]-3-methoxybenzamide and its salts |
| HU9902376 | 1999-07-15 | ||
| PCT/HU2000/000078 WO2001005791A2 (en) | 1999-07-15 | 2000-07-13 | NEW PROCESS FOR THE PREPARATION OF N-(1,1-DIMETHYLETHYL)-4-[[5'-ETHOXY-4-cis-[2-(4-MORFOLINO)ETHOXY]-2'-OXOSPIRO[CYCLOHEXAN-1,3'-[H]INDOL]-1'(2'H)-yl]-SULFONYL]-3-METHOXYBENZAMIDE AND ITS SALTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US6600039B1 true US6600039B1 (en) | 2003-07-29 |
Family
ID=89998742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/030,647 Expired - Fee Related US6600039B1 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of n-(1,1-dimethylethyl)-4-[[5′-ethoxy-4-cis[2-(4-morpholino)ethoxy]-2′-oxospiro[cyclohexan-1,3′[h]indol]1′(2′-h)-yl]-sulfonyl]-3-methoxybenzamide and its salts |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6600039B1 (en) |
| EP (1) | EP1196381B1 (en) |
| JP (1) | JP2003505389A (en) |
| CN (1) | CN1174969C (en) |
| AT (1) | ATE264842T1 (en) |
| AU (1) | AU6308100A (en) |
| BR (1) | BR0012425A (en) |
| CA (1) | CA2378087C (en) |
| CZ (1) | CZ2002145A3 (en) |
| DE (1) | DE60010083T2 (en) |
| ES (1) | ES2216927T3 (en) |
| HR (1) | HRP20020142B1 (en) |
| HU (1) | HUP9902376A3 (en) |
| MX (1) | MXPA01013344A (en) |
| PL (1) | PL195787B1 (en) |
| SK (1) | SK285818B6 (en) |
| WO (1) | WO2001005791A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040225124A1 (en) * | 2001-07-31 | 2004-11-11 | Eva Csikos | Process for the preparation of 3-spiro'cyclohexam-1,3'-'3h!indolin-2'-one! derivatives |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4823614A (en) * | 1986-04-28 | 1989-04-25 | Dahlin Erik B | Coriolis-type mass flowmeter |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997015556A1 (en) | 1995-10-24 | 1997-05-01 | Sanofi | 3-spiro-indolin-2-one derivatives as vasopressin and/or oxytocin receptor ligands |
| WO1998025901A1 (en) * | 1996-12-13 | 1998-06-18 | Sanofi | Indolin-2-one derivatives, method for preparing them and pharmaceutical compositions containing them |
-
1999
- 1999-07-15 HU HU9902376A patent/HUP9902376A3/en unknown
-
2000
- 2000-07-13 MX MXPA01013344A patent/MXPA01013344A/en active IP Right Grant
- 2000-07-13 JP JP2001511450A patent/JP2003505389A/en not_active Ceased
- 2000-07-13 EP EP00949822A patent/EP1196381B1/en not_active Expired - Lifetime
- 2000-07-13 CA CA002378087A patent/CA2378087C/en not_active Expired - Fee Related
- 2000-07-13 HR HR20020142A patent/HRP20020142B1/en not_active IP Right Cessation
- 2000-07-13 WO PCT/HU2000/000078 patent/WO2001005791A2/en not_active Ceased
- 2000-07-13 CN CNB008103143A patent/CN1174969C/en not_active Expired - Fee Related
- 2000-07-13 AU AU63081/00A patent/AU6308100A/en not_active Abandoned
- 2000-07-13 PL PL00352465A patent/PL195787B1/en not_active IP Right Cessation
- 2000-07-13 US US10/030,647 patent/US6600039B1/en not_active Expired - Fee Related
- 2000-07-13 SK SK46-2002A patent/SK285818B6/en not_active IP Right Cessation
- 2000-07-13 CZ CZ2002145A patent/CZ2002145A3/en unknown
- 2000-07-13 ES ES00949822T patent/ES2216927T3/en not_active Expired - Lifetime
- 2000-07-13 BR BR0012425-7A patent/BR0012425A/en not_active IP Right Cessation
- 2000-07-13 AT AT00949822T patent/ATE264842T1/en not_active IP Right Cessation
- 2000-07-13 DE DE60010083T patent/DE60010083T2/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997015556A1 (en) | 1995-10-24 | 1997-05-01 | Sanofi | 3-spiro-indolin-2-one derivatives as vasopressin and/or oxytocin receptor ligands |
| US5994350A (en) | 1995-10-24 | 1999-11-30 | Sanofi-Synthelabo | 3-spiro-indolin-2-one derivatives as vasopressin and/or oxytocin receptor ligands |
| WO1998025901A1 (en) * | 1996-12-13 | 1998-06-18 | Sanofi | Indolin-2-one derivatives, method for preparing them and pharmaceutical compositions containing them |
| US6090818A (en) * | 1996-12-13 | 2000-07-18 | Sanofi-Synthelabo | Indolin-2-one derivatives, method for preparing them and pharmaceutical compositions containing them |
Non-Patent Citations (1)
| Title |
|---|
| Serradeil-Le C, Lacour C, Valette G, et al. Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. J Clin Invest 1996; 98:2729-38. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040225124A1 (en) * | 2001-07-31 | 2004-11-11 | Eva Csikos | Process for the preparation of 3-spiro'cyclohexam-1,3'-'3h!indolin-2'-one! derivatives |
| US7619082B2 (en) * | 2001-07-31 | 2009-11-17 | Sanofi-Aventis | Process for the preparation of 3-spiro′cyclohexan-1,3′-′3H!indolin-2′-one! derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001005791A3 (en) | 2001-07-19 |
| HUP9902376A2 (en) | 2001-05-28 |
| DE60010083D1 (en) | 2004-05-27 |
| JP2003505389A (en) | 2003-02-12 |
| SK462002A3 (en) | 2003-03-04 |
| CA2378087C (en) | 2007-12-18 |
| CN1174969C (en) | 2004-11-10 |
| WO2001005791A2 (en) | 2001-01-25 |
| BR0012425A (en) | 2002-06-11 |
| PL195787B1 (en) | 2007-10-31 |
| MXPA01013344A (en) | 2002-08-20 |
| CZ2002145A3 (en) | 2002-11-13 |
| HRP20020142B1 (en) | 2010-09-30 |
| DE60010083T2 (en) | 2005-03-31 |
| ATE264842T1 (en) | 2004-05-15 |
| EP1196381B1 (en) | 2004-04-21 |
| HUP9902376A3 (en) | 2002-11-28 |
| ES2216927T3 (en) | 2004-11-01 |
| CA2378087A1 (en) | 2001-01-25 |
| EP1196381A2 (en) | 2002-04-17 |
| SK285818B6 (en) | 2007-09-06 |
| PL352465A1 (en) | 2003-08-25 |
| CN1420868A (en) | 2003-05-28 |
| AU6308100A (en) | 2001-02-05 |
| HU9902376D0 (en) | 1999-10-28 |
| HRP20020142A2 (en) | 2003-12-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: SANOFI-SYNTHELABO, FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HEJA, GERGELY;CSIKOS, EVA;EROSNE TAKACSY, TUNDE;AND OTHERS;REEL/FRAME:012833/0455;SIGNING DATES FROM 20020121 TO 20020123 |
|
| AS | Assignment |
Owner name: SANOFI-AVENTIS,FRANCE Free format text: CHANGE OF NAME;ASSIGNOR:SANOFI-SYNTHELABO;REEL/FRAME:016345/0189 Effective date: 20040820 Owner name: SANOFI-AVENTIS, FRANCE Free format text: CHANGE OF NAME;ASSIGNOR:SANOFI-SYNTHELABO;REEL/FRAME:016345/0189 Effective date: 20040820 |
|
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| FPAY | Fee payment |
Year of fee payment: 8 |
|
| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20150729 |